Evaluating the Contribution of TDP-43 Dysfunction and Cryptic Mis-Splicing to Alzheimer’s Disease Pathogenesis

Although Alzheimer’s disease (AD) is classically defined by the accumulation of amyloid beta and tau in the brain, a large subset of cases also accumulates the protein TDP-43, and these cases show worse disease outcomes. The mechanism by which this TDP-43 pathology influences disease severity is still unclear, but studies have revealed that there is a disruption in the protein’s ability to regulate RNA processing in the brain, resulting in an influx of transcripts that contain non-canonical “cryptic” exons. This cryptic mis-splicing is at the expense of the normal transcript, which either results in the loss of the normal encoded protein or triggers the production of an aberrant cryptic protein. We aim to investigate whether there is a change in the protein expression of some key TDP-43 targets in the brains of AD patients with TDP-43 pathology: specifically, the targets STMN2, UNC13A, and HDGFL2—all of which are the subject of current translational work in other TDP-43-related diseases. We will also use a combination of mouse modeling and immunohistochemistry to evaluate whether the endogenous activity of these proteins is disrupted in the brain upon TDP-43 dysfunction. Finally, we will explore the potential use of U7 snRNA as a form of gene therapy aimed at reversing the cryptic mis-splicing of specific targets, beginning with STMN2. Together, these experiments will help establish whether cryptic mis-splicing influences disease severity in AD—and whether we can target this aberrant event therapeutically.